Normal breast tissue changes with age. The dense fibrous and glandular breast tissue of early adulthood is replaced by increasing amounts of fat as a woman ages. After menopause, there is further involution of the glandular structures. The fatty replacement simplifies mammographic screening in older women as there is better contrast between the density of a malignancy and the density of fatty tissue. With aging, there is also a decreased tendency to develop benign breast lesions. The breast nodularity or fibrocystic change, occurring in response to cyclic hormonal changes in premenopausal women, rarely occurs in postmenopausal women unless they are receiving hormone replacement therapy. Gross cysts, which occur most commonly in women during the 15 years before menopause, are rare in the elderly. Fibroadenomas, most common between the ages of 20 and 35, are also rare in postmenopausal women. For these reasons, most newly developing breast masses in postmenopausal women are carcinomas.

Numerous studies have examined the relationship between age and extent of disease at time of breast cancer diagnosis. Stage at diagnosis is determined by two sets of factors: (1) tumor/host biology; and (2) patient/physician behavior surrounding the diagnostic process. Several studies have noted that older women have a higher likelihood of presenting with advanced disease.

The largest database is from the SEER program, which includes more than 125,000 women with breast cancer (

Table 33.3). These data indicate that a greater proportion of elderly women present with distant disease, although a smaller proportion present with regional disease. The proportion of patients who present with localized disease does not vary with age and remains about half in all age groups.

Although there is little evidence that biologic differences in tumor or host account for stage differences in older and younger patients at presentation, there is evidence that patient/physician behavior surrounding the diagnostic process is different for older women. Older women are less likely to practice breast self-examination, obtain regular breast examinations from their physicians, or undergo screening mammography. Samet et al. conducted a population-based study of 194 women with breast cancer, 65 years or older at diagnosis, to examine factors associated with stage at presentation. Factors associated with an advanced stage at presentation included longer delay between initial symptom and seeking medical care, older age, absence of breast self-examination, and poor performance on a short test of knowledge about cancer. Of the women who were symptomatic at time of diagnosis, 29% had delay of at least 3 months between symptom onset and seeking medical care. Delay in seeking care was associated with a lack of social support, a relatively common problem among the elderly.

Established prognostic factors for localized breast cancer include number of involved axillary lymph nodes, size of the primary tumor, tumor histologic and nuclear grade, lymphatic and vascular channel invasion, estrogen and progesterone receptor status, Her-2/neu overexpression, and measures of tumor proliferation such as mitotic index, Ki-67, and percent of cells in S phase of the cell cycle (

Table 33.4). In general, poor prognostic factors are less common in breast cancers of older women. Information from several large databases indicates that older women with localized disease have a higher proportion of estrogen and progesterone receptor-positive tumors and a lower incidence of Her-2/neu overexpression. The tumors of elderly women are more likely to be lower grade and have lower breast cancer cell proliferation rates. Several groups have reported an increased proportion of mucinous and papillary carcinomas, histologic subtypes with a favorable prognosis, among older women. These subtypes still account for less than 10% of breast cancers in older women, and the most common subtype in both older and younger women is infiltrating ductal carcinoma.

Age-related changes in the host may also have an effect on prognosis. In experimental animal models, some tumors behave less aggressively while others behave more aggressively in an older host. Tumors that behave less aggressively tend to be those that are less immunogenic. Several investigators have proposed that immune senescence may be the cause of this altered tumor behavior with age. Cell-mediated and humoral immune responses to foreign antigens decrease with age. In ex-perimental systems of less immunogenic tumors, manipu-lations that cause immunodeficiency actually inhibit tumor growth. An intact immune system might actually be enhancing tumor growth, possibly through production of growth factors or tumor induction of suppressor T cells that block antitumor immunity. In contrast, highly immunogenic tumors in these same experimental models behave more aggressively in hosts with immune deficiencies and in older hosts. Most human tumors are thought to be relatively nonimmunogenic.

Although there is a subset of older women with early-stage disease who have exceptionally good survival, older women have been found in general to have overall lower survival rates compared to younger women with breast cancer. Adami et al. examined the survival of 57,068 Swedish women diagnosed with breast cancer between 1960 and 1978. This database included about 98% of all cases diagnosed in Sweden during this period. The investigators found that relative survival declined markedly after age 49, and women over age 75 had the worst relative survival, although the results were not controlled for stage. Host and Lund examined the survival of 31,594 Norwegian women diagnosed with breast cancer between 1955 and 1980. This database includes almost all cases diagnosed in Norway during this period. After controlling for stage, the worst relative survival was found in patients over the age of 74 and in patients under the age of 35. In their analysis of the SEER data, Yancik et al. found that stage-specific relative survival is worse only for women aged 85 years or older diagnosed with metastatic disease.

In summary, examination of prognostic factors and tumor pathology indicates that older women, as a group, have slower-growing, more indolent, and more hormonally responsive tumors and should have a better prognosis. However, despite these findings, older women appear to have lower relative survival compared with younger women. Older women have a higher likelihood of presenting with metastatic disease, and differences in survival exist even after controlling for stage. Differences in the screening and treatment of older women may account for some of this discrepancy, and patterns of care are examined later in this chapter.